Process for producing enantiomerically enriched guaifenesin

Abstract

A tertiary amine is used to catalize the stereospecific ring-opening of chiral glycidol with o-methoxyphenol to afford high yields of enantiomerically enriched guaifenesin. The optical purity of the product may be even further enhanced by recrystallization.

We claim: 
     
       1. A method for producing enantiomerically enriched guaifenesin comprising reacting o-methoxy phenol with enantiomerically enriched glycidol in the presence of a catalytically effective amount of a tertiary amine to form the enantiomerically enriched guaifenesin. 
     
     
       2. The method of claim 1 wherein said reaction is performed at a temperature of from 50° C. to 150° C. 
     
     
       3. The method of claim 1 wherein the enantiomerically enriched glycidol has an e.e. value of at least 85%. 
     
     
       4. The method of claim 1 wherein the molar ratio of o-methoxy phenol to enantiomerically enriched glycidol is from 2:1 to 1:2. 
     
     
       5. The method of claim 1 wherein the tertiary amine is present in an amount of from 0.5 to 10 mole percent based on the molar amount of o-methoxy phenol. 
     
     
       6. The method of claim 1 wherein the tertiary amine is selected from the group consisting of trialkylamines, pyridines, dialkyl anilines, and quinolines. 
     
     
       7. The method of claim 1 wherein said reaction is performed in the presence of a non-acidic inert solvent. 
     
     
       8. The method of claim 1 comprising an additional step of recrystallizing the enantomerically enriched guaifenesin from a solvent to higher optical purity. 
     
     
       9. The method of claim 8 wherein the solvent is ethanol. 
     
     
       10. A method for producing enantiomerically enriched guaifenesin having an e.e. value of at least 85% comprising reacting o-methoxyphenol with enantiomerically enriched glycidol at a molar ratio of from 2:1 to 1:2 in the presence of from 0.5 to 10 moles of a tertiary amine per mole of o-methoxy phenol at a temperature of from 50° to 150° C. to form the enantiomerically enriched guaifenesin. 
     
     
       11. The method of claim 10 comprising an additional step of recrystallizing the enantiomerically enriched guaifenesin from a solvent to higher optical purity. 
     
     
       12. The method of claim 10 wherein the predominate enantiomer present in the enantiomerically enriched guaifenesin is the S isomer. 
     
     
       13. The method of claim 10 wherein the predominate enantiomer present in the enantiomerically enriched guaifenesin is the R isomer. 
     
     
       14. A method for producing guaifenesin of high optical purity comprising reacting o-methoxy phenol with enantiomerically enriched glycidol in the presence of a tertiary amine to form enantiomerically enriched guaifenesin and recrystallizing the enantiomerically enriched guaifenesin from a solvent to higher optical purity.